A high-efficiency δ 9,11 -The preparation method of canrenone

A canrenone and high-efficiency technology, applied in the field of high-efficiency Δ9,11-canrenone preparation, can solve the problems of increased impurity content, long process route, cumbersome process, etc., and achieves low production cost, high commercial competitiveness, and availability. Actionable effect

Active Publication Date: 2021-05-25
ZHEJIANG SHENZHOU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The process route of this method is long and the process is cumbersome. Because it is fermented, sulfonated, and desulfonated after the formation of the 17-position lactone ring, the 17-position lactone ring will affect the fermentation, sulfonate, and desulfonate. Detrimental effects of ester reactions leading to increased impurity levels and lower yields

Method used

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  • A high-efficiency δ <sup>9,11</sup> -The preparation method of canrenone
  • A high-efficiency δ <sup>9,11</sup> -The preparation method of canrenone
  • A high-efficiency δ <sup>9,11</sup> -The preparation method of canrenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1Δ 9,11 -The preparation method of canrenone, concrete steps are as follows:

[0035] 1) Put 100ml of sulfuric acid solution with a mass concentration of 20% into a three-necked bottle, put in 10g of 9α-hydroxy-4-androstene-3,17dione, and keep warm at 60°C for reaction. Methane extraction, washing with water, concentration, water analysis, filtration, and drying to obtain Δ 9,11 -4-androstene-3,17dione 9.1 g.

[0036] 2) Put Δ 9,11 -4-Androstene-3,17dione was put into 4.5ml of methanol, 3.5ml of trimethyl orthoformate and 0.09g of pyridine hydrochloride were added, and the temperature was kept at 20°C for reaction. After the reaction was completed, it was filtered and dried to obtain 3-methanol Oxy-androst-3,5,9(11)-trien-17-one 9.2 g.

[0037] 3) Put 1.2g sodium methoxide and 12.9g trimethylsulfonium iodide into the reaction bottle, 9.2g 3-methoxy-androst-3,5,9(11)-triene-17-one, put 92ml Dimethyl sulfoxide, keep warm at 0°C for reaction, after the reactio...

Embodiment 2

[0041] Example 2Δ 9,11 -The preparation method of canrenone, concrete steps are as follows:

[0042] 1) Put 20ml of sulfuric acid solution with a mass concentration of 80% into the three-necked bottle, cool down to 10°C, put in 10g of 9α-hydroxy-4-androstene-3,17dione, keep warm at 10°C for reaction, after the reaction is completed, water analysis , extracted with 200ml dichloromethane, washed with water, concentrated, water analyzed, filtered and dried to obtain Δ 9,11 -4-androstene-3,17-dione 9.2 g.

[0043] 2) The 9.2gΔ 9,11 -4-androstene-3,17dione was put into 92ml tetrahydrofuran, added 16.2ml pyrrolidine, 0.46g pyridinium hydrobromide, and kept at 50°C for reaction. After the reaction was completed, it was filtered and dried to obtain 3-pyrrolyl-androstene Ste-3,5,9(11)-trien-17-one 9.48 g.

[0044] 3) Put 5.36g of potassium ethylate and 10.05g of trimethylsulfonium bromide into the reaction bottle, 9.48g of 3-pyrrolyl-androst-3,5,9(11)-trien-17-one, and put into 19m...

Embodiment 3

[0048] Example 3Δ 9,11 -The preparation method of canrenone, concrete steps are as follows:

[0049] 1) Put 50ml of sulfuric acid solution with a mass concentration of 50% into a three-neck flask, put in 10g of 9α-hydroxy-4-androstene-3,17dione, and keep warm at 40°C for reaction. After the reaction is completed, analyze with water and extract with 100ml of toluene , washed with water, concentrated, hydrolyzed, filtered, and dried to obtain Δ 9,11 -4-androstene-3,17dione 9.0 g.

[0050] 2) Add 9.0gΔ 9,11 -4-Androstene-3,17-dione was put into 27ml of tetrahydrofuran, 26.4ml of triethyl orthoformate and 0.9g of p-toluenesulfonic acid were added, and the temperature was kept at 40°C for reaction. After the reaction was completed, it was filtered and dried to obtain 3-ethyl Oxy-androst-3,5,9(11)-trien-17-one 9.0 g.

[0051] 3) Put 10.2g potassium tert-butoxide and 15.3g trimethylsulfonium chloride into the reaction flask, 9g 3-ethoxy-androst-3,5,9(11)-triene-17-one, put 27ml ...

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Abstract

The invention discloses a high-efficiency Δ 9,11 A preparation method of canrenone belongs to the technical field of preparation of intermediates of medicines. The method is based on 9α-hydroxy-4-androstenedione as a raw material, and the 9-position hydroxyl group is first eliminated by dehydration reaction to generate Δ 9,11 Double bond, then protect the 3-position carbonyl group, then epoxidize the 17-position carbonyl group, and condense with malonic acid diester to form a lactone ring, and obtain Δ after oxidative decarboxylation or decarboxylation oxidation reaction 9,11 ‑Canrenone, the raw materials of the method of the present invention are cheap and easy to obtain, the cost is low, the reaction products involved in each step are easy to purify, and the total mass yield of the final product is higher than 80%. The method of the present invention has strong operability and extremely high commercial Competitive, suitable for industrialized large-scale production, and has good economic benefits.

Description

technical field [0001] The invention relates to the technical field of preparation of intermediates of medicines, in particular to a high-efficiency Δ 9,11 - A process for the preparation of canrenone. Background technique [0002] Δ 9,11 -Canrenone is an important intermediate of eplerenone. Eplerenone is a new type of selective aldosterone receptor antagonist, which has stronger aldosterone antagonism than spironolactone, and has extremely low affinity for androgen and progesterone receptors , less adverse reactions, definite curative effect on the treatment of hypertension, heart failure and myocardial infarction, fewer adverse reactions, good tolerance, is a good substitute drug for spironolactone. Therefore, the research on Δ9,11-canrenone has also promoted the development of these fields. [0003] Existing Δ 9,11 The preparation process of -canrenone is mainly based on diketone as raw material, first synthesize canrenone, and then ferment the 11-position to form 11...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J21/00
CPCC07J21/003
Inventor 黄橙橙邵振平王友富王荣王炳乾王洪福雷灵芝
Owner ZHEJIANG SHENZHOU PHARMA
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